Spinal and Bulbar Muscular Atrophy (SBMA, Kennedy's Disease) is an X-linked progressive neurodegenerative disease affecting the proximal spinal and bulbar motoneurons. Patients present in midlife with weakness of the limbs and facial fasciculation that often progresses to dysarthria and dysphagia, complications of which can lead to fatality. SBMA patients also commonly suffer from mild androgen insensitivity, presenting with symptoms including gynecomastia, testicular atrophy, and decreased fertility. SBMA is caused by an expansion of a polymorphic CAG trinucleotide repeat in the Androgen Receptor (AR) gene, classifying the disease as one of the nine polyglutamine (polyQ) disorders. PolyQ expansion renders the host protein toxic, resulting in the formation of mutant protein aggregates and cell death. The commonalities in the nature of the mutation and the presentation of the different polyQ disorders suggest the presence of a common pathogenic mechanism. Nonetheless, this mechanism has remained elusive and to date there are no cures or even effective therapeutics for many of these diseases. Studying the pathogenesis of one polyQ disorder, namely SBMA, should hopefully shed some light on the pathogenic mechanisms underlying all nine diseases. Furthermore, the only SBMA-specific therapeutics to have undergone clinical trials are aimed at reducing the androgen insensitivity would be beneficial in maintaining patient quality-of-life. This proposal therefore investigates the role of the serine/threonine protein kinase Nemo-Like Kinase (NLK) in the pathogenesis of SBMA with the hope that NLK will prove a viable drug target in the development of future therapeutics. Specifically, this application addresses the hypothesis that NLK promotes the SBMA disease condition via interacting with and modulating the polyQ-expanded mutant AR. To test this idea, the effect of NLK co- expression on an SBMA cellular model will be investigated using protein expression, immunofluorescence, and cytotoxicity techniques. Both established and novel Drosophila models of SBMA will be employed to determine if there is a genetic interaction between NLK and the mutant AR using both photoreceptor neurons and the motor neurons/neuromuscular junction as model tissues. Finally, the molecular mechanism underlying the interaction between NLK and AR will be investigated using transcription assays, molecular biology and genetic techniques in cellular and Drosophila models. Through this integrated approach of genetics, molecular biology, and in vivo disease models, this proposal seeks to define the role of NLK in promoting the SBMA disease condition, paving the way for future mammalian studies and ultimately allowing for the development of novel, non-anti-androgen therapeutics to treat this devastating disorder. PUBLIC HEALTH RELEVANCE: The polyglutamine diseases represent a class of devastating neurodegenerative disorders that afflict millions of people worldwide. Despite the fact that these diseases arise from a similar mutation and share various symptomatic features, the underlying pathogenic mechanisms remain poorly understood and effective therapeutics are therefore unavailable for many of these conditions1. This proposal explores the role of Nemo- Like Kinase (NLK) in the pathogenesis of one polyglutamine disease, Spinal and Bulbar Muscular Atrophy, with the aim that NLK may prove to be a target protein in the development of novel therapeutics.